Overexpression of PtoCYCD3;3 Promotes Growth and Causes Leaf Wrinkle and Branch Appearance in Populus.

D-type cyclin (cyclin D, CYCD), combined with cyclin-dependent kinases (CDKs), participates in the regulation of cell cycle G1/S transition and plays an important role in cell division and proliferation. CYCD could affect the growth and development of herbaceous plants, such as Arabidopsis thaliana, by regulating the cell cycle process. However, its research in wood plants (e.g., poplar) is poor. Phylogenetic analysis showed that in Populus trichocarpa, CYCD3 genes expanded to six members, namely PtCYCD3;1-6. P. tomentosa CYCD3 genes were amplified based on the CDS region of P. trichocarpa CYCD3 genes. PtoCYCD3;3 showed the highest expression in the shoot tip, and the higher expression in young leaves among all members. Therefore, this gene was selected for further study. The overexpression of PtoCYCD3;3 in plants demonstrated obvious morphological changes during the observation period. The leaves became enlarged and wrinkled, the stems thickened and elongated, and multiple branches were formed by the plants. Anatomical study showed that in addition to promoting the differentiation of cambium tissues and the expansion of stem vessel cells, PtoCYCD3;3 facilitated the division of leaf adaxial epidermal cells and palisade tissue cells. Yeast two-hybrid experiment exhibited that 12 PtoCDK proteins could interact with PtoCYCD3;3, of which the strongest interaction strength was PtoCDKE;2, whereas the weakest was PtoCDKG;3. Molecular docking experiments further verified the force strength of PtoCDKE;2 and PtoCDKG;3 with PtoCYCD3;3. In summary, these results indicated that the overexpression of PtoCYCD3;3 significantly promoted the vegetative growth of Populus, and PtoCYCD3;3 may interact with different types of CDK proteins to regulate cell cycle processes.

Mendelian randomization analysis reveals causality of inflammatory bowel disease on risks of Henoch-Schönlein purpura and immune thrombocytopenia.

BACKGROUND: Emerging clinical evidence has been discovered associating Inflammatory bowel disease (IBD) with Henoch-Schönlein purpura (HSP) and immune thrombocytopenia (ITP). However, it is unclear whether a cause-effect relationship exists between them. We aimed to examine the casual effect of IBD on the risk of HSP and ITP. METHODS: Based on summary statistics from International IBD Genetics (IIBDG) Consortium and FinnGen study, a two-sample Mendelian randomization study was carried out to determine whether IBD including ulcerative colitis (UC) and Crohn's disease (CD) is causally related to HSP, ITP or secondary thrombocytopenia. To support the results, a variety of sensitivity analyses were performed. RESULTS: Significant causal relationships between IBD and HSP (odds ratios = 1.20, 95% confidence interval: 1.07-1.36, adjusted P = 0.006) and ITP (odds ratios =1.22, 95% confidence interval: 1.08-1.38, adjusted P = 0.006) were found. Both genetically predicted UC and CD were positively related with ITP, while CD alone may be responsible for the higher risk of HSP. Besides, no significant association was observed between IBD and secondary thrombocytopenia. CONCLUSIONS: The results of this Mendelian randomization study supported the causal association of IBD with HSP and ITP. Taken together, our findings may present implications for management of IBD.

RUNX1 promotes angiogenesis in colorectal cancer by regulating the crosstalk between tumor cells and tumor associated macrophages.

Colorectal cancer (CRC) is a common malignancy worldwide. Angiogenesis and metastasis are the critical hallmarks of malignant tumor. Runt-related transcription factor 1 (RUNX1), an efficient transcription factor, facilitates CRC proliferation, metastasis and chemotherapy resistance. We aimed to investigate the RUNX1 mediated crosstalk between tumor cells and M2 polarized tumor associated macrophages (TAMs) in CRC, as well as its relationship with neoplastic angiogenesis. We found that RUNX1 recruited macrophages and induced M2 polarized TAMs in CRC by promoting the production of chemokine 2 (CCL2) and the activation of Hedgehog pathway. In addition, we found that the M2 macrophage-specific generated cytokine, platelet-derived growth factor (PDGF)-BB, promoted vessel formation both in vitro and vivo. PDGF-BB was also found to enhance the expression of RUNX1 in CRC cell lines, and promote its migration and invasion in vitro. A positive feedback loop of RUNX1 and PDGF-BB was thus formed. In conclusion, our data suggest that RUNX1 promotes CRC angiogenesis by regulating M2 macrophages during the complex crosstalk between tumor cells and TAMs. This observation provides a potential combined therapy strategy targeting RUNX1 and TAMs-related PDGF-BB in CRC.

Management of intractable epistaxis in patients who received radiation therapy for nasopharyngeal carcinoma.

To report clinical manifestations, bleeding point localization, and outcomes of management in 16 patients with 16 instances of intractable epistaxis after radiation therapy for nasopharyngeal carcinoma. Retrospective chart review of 16 patients with nasopharyngeal carcinoma (mean age 52.06 ± 14.37 years) with 16 instances of intractable epistaxis during the past 5 years, whose diagnosis was confirmed by angiography (n = 10) or MRI/CT imaging studies and clinical manifestations (n = 6). The mean radiation dose to the affected carotid artery was 101.37 ± 34.85 Gy. Bleeding points were detected in the internal carotid artery (n = 8) or external carotid artery (n = 8). Detachable balloons were used in one affected artery for vascular occlusion; six were treated using an absorbable gelatin sponge (n = 4) or microcoils (diameter 1 mm) (n = 2). Endovascular embolization was successful in seven radiation carotid blowout syndromes with cessation of hemorrhage. One patient underwent external carotid artery ligation and one patient recovered without treatment. The clinical follow-up was 3 months. Therapeutic endovascular embolization of intractable epistaxis is both efficient and safe. It should be considered as the primary treatment modality in intractable epistaxis of nasopharyngeal carcinoma.

Targeted splicing therapy: new strategies for colorectal cancer.

RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.

Research progress on the mechanism of cholesterol-25-hydroxylase in intestinal immunity.

Inflammatory bowel disease (IBD), a general term encompassing Crohn's disease (CD) and ulcerative colitis (UC), and other conditions, is a chronic and relapsing autoimmune disease that can occur in any part of the digestive tract. While the cause of IBD remains unclear, it is acknowledged that the disease has much to do with the dysregulation of intestinal immunity. In the intestinal immune regulatory system, Cholesterol-25-hydroxylase (CH25H) plays an important role in regulating the function of immune cells and lipid metabolism through catalyzing the oxidation of cholesterol into 25-hydroxycholesterol (25-HC). Specifically, CH25H focuses its mechanism of regulating the inflammatory response, signal transduction and cell migration on various types of immune cells by binding to relevant receptors, and the mechanism of regulating lipid metabolism and immune cell function via the transcription factor Sterol Regulator-Binding Protein. Based on this foundation, this article will review the function of CH25H in intestinal immunity, aiming to provide evidence for supporting the discovery of early diagnostic and treatment targets for IBD.

Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota.

Inflammatory bowel disease (IBD), characterized primarily by gastrointestinal inflammation, predominantly manifests as Crohn's disease (CD) and ulcerative colitis (UC). It is acknowledged that Inflammation plays a significant role in cancer development and patients with IBD have an increased risk of various cancers. The progression from inflammation to carcinogenesis in IBD is a result of the interplay between immune cells, gut microbiota, and carcinogenic signaling pathways in epithelial cells. Long-term chronic inflammation can lead to the accumulation of mutations in epithelial cells and the abnormal activation of carcinogenic signaling pathways. Furthermore, Immune cells play a pivotal role in both the acute and chronic phases of IBD, contributing to the transformation from inflammation to tumorigenesis. And patients with IBD frequently exhibit dysbiosis of the intestinal microbiome. Disruption of the gut microbiota and subsequent immune dysregulation are central to the pathogenesis of both IBD and colitis associated colorectal cancer (CAC). The proactive management of inflammation combined with regular endoscopic and tumor screenings represents the most direct and effective strategy to prevent the IBD-associated cancer.

Discovery of specific catalytic activity toward IAA/FA by LaSABATHs based on genome-wide phylogenetic and enzymatic analysis of SABATH gene family from Larix kaempferi.

The SABATH methyltransferases catalyze methylation of small-molecule metabolites, which participate in plant growth, development and defense response. Given lack of genome-wide studies on gymnosperms SABATH family, the formation and functional differentiation mechanism of the Larix kaempferi SABATH gene family was systematically and exhaustively explored by analyzing gene sequence characteristics, phylogenetic relationship, expression pattern, and enzyme activities. Phylogenetic analysis showed that 247 SABATH genes from 14 land plants were divided into 4 clades, and lineage-specific gene duplication events were important factors that contributed to the evolution of the SABATH gene family in gymnosperms and angiosperms. Substrate specificity analysis of 18 Larix SABATH proteins showed that LaSABATHs could catalyze O-methylation of indole-3-acetic acid (IAA) and farnesic acid (FA), N-methylation of theobromine, and S-methylation of thiobenzoic acid. Furthermore, only LaSABATH2 and LaSABATH29 could catalyze O-methylation of FA, and only LaSABATH30 could catalyze O-methylation of IAA. Homology modeling and molecular docking studies showed the hydrogen bond formed between the His188 of LaSABATH30 and IAA and the noticeable hydrophobic IAA-binding pocket may be helpful for IAA methylation. In this study, identification of proteins with significant specific catalytic activity toward FA and IAA provided high-quality candidate genes for forest genetics and breeding.

Molecular subtypes and tumor microenvironment infiltration signatures based on cuproptosis-related genes in colon cancer.

Background: Colon cancer is one of the common cancers, and its prognosis remains to be improved. The role of cuproptosis as a newly discovered form of cell death in the development of colon cancer has not been determined. Methods: Based on 983 colon cancer samples in the TCGA database and the GEO database, we performed a comprehensive genomic analysis to explore the molecular subtypes mediated by cuproptosis-related genes. Single-sample gene set enrichment analysis (ssGSEA) was utilized to quantify the relative abundance of each cell infiltrate in the TME. A risk score was established using least absolute shrinkage and selection operator regression (LASSO), and its predictive ability for colon cancer patients was verified to explore its guiding value for treatment. Results: We identified two distinct cuproptosis-related molecular subtypes in colon cancer. These two distinct molecular subtypes can predict clinicopathological features, prognosis, TME activity, and immune-infiltrating cells. A risk model was developed and its predictive ability was verified. Compared with patients in the high-risk score group, patients in the low-risk score group were characterized by lower tumor microenvironment score, higher stem cell activity, lower tumor mutational burden, lower microsatellite instability, higher sensitivity to chemotherapeutics, and better immunotherapy efficacy. Conclusion: This study contributes to understanding the molecular characteristics of cuproptosis-related subtypes. We demonstrate a critical role for cuproptosis genes in colon cancer s in the TME. Our study contributes to the development of individualized treatment regimens for colon cancer.

Inherited CHEK2 p.H371Y mutation in solitary rectal ulcer syndrome among familial patients: A case report.

BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a rare rectal disease with unknown etiology. Data on the genetic background in SRUS is lacking. CASE SUMMARY: Here, we report the first case of SRUS in a mother-son relationship. Gene sequencing was conducted on the whole family, which revealed an inherited CHEK2 p.H371Y mutation. The experiment preliminarily revealed that the CHEK2 mutation did not affect the expression of CHEK2 protein, but affected the function of CHEK2, resulting in the expression level changes of downstream genes such as CDC25A. CONCLUSION: SRUS is a genetic susceptibility disease where CHEK2 p.H371Y mutation may play a crucial role in the development and prognosis of SRUS.

Study on the interaction preference between CYCD subclass and CDK family members at the poplar genome level.

Cyclin-dependent kinases (CDKs) control the progression of the cell cycle. D-type cyclin (CYCD) is generally believed to form a complex with CDK and control the G1/S transition. In plants, CYCD and CDK gene families can be divided into 6 (D1-D7) and 7 (CDKA-CDKG) subclasses, respectively. Different subclasses in the CYCD and CDK families have different numbers, structures and functions. In some heterologous woody plants, the functions of these subclass family members remain unclear. In this study, 43 CYCD and 27 CDK gene family members were identified in the allodiploid Populus tomentosa Carr. Phylogenetic analysis suggested that these CYCDs and CDKs were divided into 6 and 7 subclasses, respectively, which were the same as other species. The analysis of protein properties, gene structure, motifs, domains, cis-acting elements and tissue-specific expression of all members of these CYCDs and CDKs showed that the differences between members of different subclasses varied widely, but members of the same subclass especially in the CDK gene family were very similar. These findings also demonstrated a strong correlation between CYCD and CDK gene family members in response to hormones and specific expression. The collinear analysis of P. tomentosa, Populus trichocarpa and Arabidopsis thaliana showed that the expansion patterns of CYCD and CDK gene families were predominantly whole genome duplications (WGD). The protein interaction prediction results of different subclasses of CYCD and CDKs showed that the interaction between different subclasses of CYCD and CDKs was significantly different. Our previous study found that transgenic PtoCYCD2;1 and PtoCYCD3;3 poplars exhibited opposite phenotypes. Y2H and BIFC results showed that the interaction between PtoCYCD2;1 and PtoCYCD3;3 was significantly different with CDKs. This finding might suggest that the functional differences of different CYCD subclasses in plant growth and development were closely related to the different interactions between CYCD and CDK. Our results provide a good idea and direction for the functional study of CYCD and CDK proteins in woody plants.

Diffusion Abnormality in Temporal Lobe Epilepsy Patients With Sleep Disorders: A Diffusion Kurtosis Imaging Study.

Background: Patients with temporal lobe epilepsy (TLE) frequently complain of poor sleep quality, which is a condition that clinicians are typically neglecting. In this study, Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Athens Insomnia Scale (AIS) were used to assess the sleep status of patients with temporal lobe epilepsy (TLE). Simultaneously diffusion kurtosis imaging (DKI) was applied to examine the white matter microstructure abnormalities in patients with TLE and sleep disorders. Methods: TLE patients who have been diagnosed in the cardio-cerebrovascular ward of the Yanan University Affiliated Hospital from October 2020 to August 2021 were recruited. Finally, 51 patients and 30 healthy controls were enrolled in our study, with all subjects completing the sleep evaluation questionnaire and undergoing a DKI examination. Using independent sample t-test, analysis of variance (ANOVA), and Mann-Whitney U test to compare groups. Results: Thirty patients (58.82%) complained of long-term sleep difficulties. The overall differences among the evaluation of AIS, ESS, and PSQI are significant (P = 0.00, P = 0.00, P = 0.03). The scores of AIS, ESS in Left and Right-TLE (L/R-TLE) with sleep disorders, as well as PSQI in L-TLE, are statistically higher than the control group (P = 0.00, P = 0.00, P = 0.00, P = 0.00, P = 0.02). L-TLE with sleep disorders showed decreased MK on affected sides (P = 0.01). However, statistical differences in MD and FA have not been observed (P = 0.34, P = 0.06); R-TLE with sleep disorders showed significantly decreased MK and increased MD on affected sides (P = 0.00, P = 0.00), but FA's statistical difference has not been observed (P = 0.20). Conclusions: TLE patients with sleep disorders have different DKI parameters than individuals who do not have sleep issues. During this process, the kurtosis parameter (MK) was more sensitive than the tensor parameters (MD, FA) in detecting the patient's aberrant white matter diffusion. DKI may be a better choice for in vivo investigation of anomalous craniocerebral water diffusion.

DDX39B contributes to the proliferation of colorectal cancer through direct binding to CDK6/CCND1.

DDX39B (also called UAP56 or BAT1) which is a kind of DEAD-box family helicase plays pivotal roles in mRNA binding, splicing, and export. It has been found upregulated in many kinds of tumors as an oncogene. Nevertheless, the underlying molecular mechanisms of DDX39B in the proliferation of human colorectal cancer (CRC) remain fairly elusive. In our study, function experiments including the CCK8 and colony formation assay revealed that DDX39B facilitates CRC proliferation in vitro. DDX39B knockdown cells were administered for the orthotopic CRC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry (IHC) was performed to prove that DDX39B can also facilitates CRC proliferation in vivo. Flow cytometry demonstrated that DDX39B promotes the proliferation of CRC cells by driving the cell cycle from G0/G1 phase to the S phase. Mechanistically, RNA-binding protein immunoprecipitation-sequencing (RIP-seq) confirmed that DDX39B binds directly to the first exon of the CDK6/CCND1 pre-mRNA and upregulates their expression. Splicing experiments in vitro using a RT-PCR and gel electrophoresis assay confirmed that DDX39B promotes CDK6/CCND1 pre-mRNA splicing. Rescue experiments indicated that CDK6/CCND1 is a downstream effector of DDX39B-mediated CRC cell proliferation. Collectively, our results demonstrated that DDX39B and CDK6/CCND1 direct interactions serve as a CRC proliferation promoter, which can accelerate the G1/S phase transition to enhance CRC proliferation, and can offer novel and emerging treatment strategies targeting this cell proliferation-promoting gene.

Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia.

Background: The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear. Methods: We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package edgeR was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein-protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results. Results: A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways. Conclusion: The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.

The DDX39B/FUT3/TGFßR-I axis promotes tumor metastasis and EMT in colorectal cancer.

DDX39B is a member of the DEAD box (DDX) RNA helicase family required for nearly all cellular RNA metabolic processes. The exact role and potential molecular mechanism of DDX39B in the progression of human colorectal cancer (CRC) remain to be investigated. In the present study, we demonstrate that DDX39B expression is higher in CRC tissues than in adjacent normal tissues. Gain- and loss-of-function assays revealed that DDX39B facilitates CRC metastasis in vivo and in vitro. Mechanistically, RNA-sequencing (RNA-seq) and RNA-binding protein immunoprecipitation-sequencing (RIP-seq) showed that DDX39B binds directly to the FUT3 pre-mRNA and upregulates FUT3 expression. Splicing experiments in vitro using a Minigene assay confirmed that DDX39B promotes FUT3 pre-mRNA splicing. A nuclear and cytoplasmic RNA separation assay indicates that DDX39B enhances the mRNA export of FUT3. Upregulation of FUT3 accelerates the fucosylation of TGFßR-I, which activates the TGFß signaling pathway and eventually drives the epithelial-mesenchymal transition (EMT) program and contributes to CRC progression. These findings not only provide new insight into the role of DDX39B in mRNA splicing and export as well as in tumorigenesis, but also shed light on the effects of aberrant fucosylation on CRC progression.

RUNX1 regulates the proliferation and chemoresistance of colorectal cancer through the Hedgehog signaling pathway.

Background: Chemoresistance is one of the main causes of recurrence in colorectal cancer (CRC) patients and leads to a poor prognosis. To characterize RUNX1 expression in colorectal cancer (CRC) and elucidate its mechanistic involvement in the tumor biology of this disease. Methods: The expression of RUNX1 in CRC and normal tissues was detected by bioinformatics analysis. Cell proliferation was measured by CCK-8 and clonogenic assays. In vivo tumor progression was assessed with a xenograft mouse model. Cell drug sensitivity tests and flow cytometry were performed to analyze CRC cell chemoresistance. RUNX1, key molecules of the Hedgehog signaling pathway, and ABCG2 were detected by qRT-PCR and Western blotting. Results: RUNX1 expression is upregulated in CRC tissues. RUNX1 enhanced CRC cell resistance to 5-fluorouracil (5-FU), promoted proliferation, and inhibited 5-FU-induced apoptosis. Mechanistically, RUNX1 can activate the Hedgehog signaling pathway and promote the expression of ABCG2 in CRC cells. Conclusions: Our study demonstrated that RUNX1 promotes CRC proliferation and chemoresistance by activating the Hedgehog signaling pathway and ABCG2 expression.

MiR-452-5p promotes colorectal cancer progression by regulating an ERK/MAPK positive feedback loop.

BACKGROUND: MiR-452-5p plays an essential role in the development of a variety of tumors, but little is known about its biological function and mechanism in colorectal cancer (CRC). METHODS: The expression levels of miR-452-5p in CRC tissues and cells were detected by real-time quantitative PCR (qRT-PCR). Besides, the biological effects of miR-452-5p on CRC were investigated by functional experiments in vitro and in vivo. Furthermore, bioinformatics analysis, dual-luciferase reporter assay, chromatin immunecipitation assay, western blotting and recovery experiments were implemented to investigate the underlying molecular mechanism. RESULTS: The expression level of miR-452-5p was up-regulated in CRC tissues. MiR-452-5p promoted CRC cell proliferation, cell cycle transition and chemoresistance, and inhibited cell apoptosis. Moreover, miR-452-5p directly targeted PKN2 and DUSP6 and subsequently activated the ERK/MAPK signaling pathway, and it was transcriptionally regulated by c-Jun. CONCLUSION: To conclude, miR-452-5p expression is up-regulated in CRC, which promotes the progression of CRC by activating the miR-452-5p-PKN2/DUSP6-c-Jun positive feedback loop. These findings indicate that miR-452-5p may act as a potential therapeutic target and clinical response biomarker for CRC.

VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression.

Recent epidemiological and preclinical evidence indicates that vitamin D3 inhibits colorectal cancer (CRC) progression, but the mechanism has not been completely elucidated. This study was designed to determine the protective effects of vitamin D3 and identify crucial targets and regulatory mechanisms in CRC. First, we confirmed that 1,25(OH)2D3, the active form of vitamin D3, suppressed the aggressive phenotype of CRC in vitro and in vivo. Based on a network pharmacological analysis, N-acetyltransferase 2 (NAT2) was identified as a potential target of vitamin D3 against CRC. Clinical data of CRC patients from our hospital and bioinformatics analysis by online databases indicated that NAT2 was downregulated in CRC specimens and that the lower expression of NAT2 was correlated with a higher metastasis risk and lower survival rate of CRC patients. Furthermore, we found that NAT2 suppressed the proliferation and migration capacity of CRC cells, and the JAK1/STAT3 signaling pathway might be the underlying mechanism. Moreover, Western blot and immunofluorescence staining assays demonstrated that 1,25(OH)2D3 promoted NAT2 expression, and the chromatin immunoprecipitation assay indicated that the vitamin D receptor (VDR) transcriptionally regulated NAT2. These findings expand the potential uses of vitamin D3 against CRC and introduce VDR signaling via the enzyme NAT2 as a potential diagnostic and therapeutic target for CRC.

CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling.

BACKGROUND: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. METHODS: The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. RESULTS: Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. CONCLUSIONS: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

CTCF promotes colorectal cancer cell proliferation and chemotherapy resistance to 5-FU via the P53-Hedgehog axis.

CTCF is overexpressed in several cancers and plays crucial roles in regulating aggressiveness, but little is known about whether CTCF drives colorectal cancer progression. Here, we identified a tumor-promoting role for CTCF in colorectal cancer. Our study demonstrated that CTCF was upregulated in colorectal cancer specimens compared with adjacent noncancerous colorectal tissues. The overexpression of CTCF promoted colorectal cancer cell proliferation and tumor growth, while the opposite effects were observed in CTCF knockdown cells. Increased GLI1, Shh, PTCH1, and PTCH2 levels were observed in CTCF-overexpressing cells using western blot analyses. CCK-8 and apoptosis assays revealed that 5-fluorouracil chemosensitivity was negatively associated with CTCF expression. Furthermore, we identified that P53 is a direct transcriptional target gene of CTCF in colorectal cancer. Western blot and nuclear extract assays showed that inhibition of P53 can counteract Hedgehog signaling pathway repression induced by CTCF knockdown. In conclusion, we uncovered a crucial role for CTCF regulation that possibly involves the P53-Hedgehog axis and highlighted the clinical utility of colorectal cancer-specific potential therapeutic target as disease progression or clinical response biomarkers.